title: Suppression of Alzheimer's disease-related phenotypes by geranylgeranylacetone in mice.
abstract: Amyloid-β peptide (Aβ) plays an important role in the pathogenesis of Alzheimer's disease (AD). Aβ is generated by the secretase-mediated proteolysis of β-amyloid precursor protein (APP), and cleared by enzyme-mediated degradation and phagocytosis. Transforming growth factor (TGF)-β1 stimulates this phagocytosis. We recently reported that the APP23 mouse model for AD showed fewer AD-related phenotypes when these animals were crossed with transgenic mice expressing heat shock protein (HSP) 70. We here examined the effect of geranylgeranylacetone, an inducer of HSP70 expression, on the AD-related phenotypes. Repeated oral administration of geranylgeranylacetone to APP23 mice for 9 months not only improved cognitive function but also decreased levels of Aβ, Aβ plaque deposition and synaptic loss. The treatment also up-regulated the expression of an Aβ-degrading enzyme and TGF-β1 but did not affect the maturation of APP and secretase activities. These outcomes were similar to those observed in APP23 mice genetically modified to overexpress HSP70. Although the repeated oral administration of geranylgeranylacetone did not increase the level of HSP70 in the brain, a single oral administration of geranylgeranylacetone significantly increased the level of HSP70 when Aβ was concomitantly injected directly into the hippocampus. Since geranylgeranylacetone has already been approved for use as an anti-ulcer drug and its safety in humans has been confirmed, we propose that this drug be considered as a candidate drug for the prevention of AD.
authors.affiliation: Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Hoshino
authors.forename: Koichiro
authors.initials: K
authors.lastname: Suzuki
authors.forename: Takahide
authors.initials: T
authors.lastname: Matsushima
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamakawa
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Suzuki
authors.forename: Tohru
authors.initials: T
authors.lastname: Mizushima
mesh_terms: D000284:Administration, Oral; D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003071:Cognition / Q000187:drug effects; D004195:Disease Models, Animal; D004224:Diterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015870:Gene Expression; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D009451:Neuroeffector Junction / Q000187:drug effects / Q000473:pathology; D010641:Phenotype
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004224:Diterpenes; D018840:HSP70 Heat-Shock Proteins; D053829:Amyloid Precursor Protein Secretases; C031049:geranylgeranylacetone